Differential Diagnosis of Alzheimer’s Disease

ALZHEIMER'S DISEASE UPDATE

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DIFFERENTIAL DIAGNOSIS OF ALZHEIMER'S DISEASE John C. Morris, MD

One of the most important problems in geriatrics today, Alzheimer's disease (AD) is the most prevalent of the many conditions that produce dementia as a symptom. Differences in definitions of dementia, case-finding procedures, and other methodologies result in variable estimates of the frequency of AD, but prevalence rates are generally in the range of 5% to 10% for the total population aged 65 years and older. Prevalence increases exponentially with age such that between 25% and 50% of the "oldest old" (persons aged 85 years or more) are a f f e ~ t e d . ~The ~ , ' ~"graying ~ of America" ensures that AD will continue to be a major public health problem; the annual cost, direct and indirect, of AD in the US is already On an individual level, the progressive cognitive deteriora$58 billi~n.~' tion and ensuing disability associated with AD force emotional, legal, and economic adjustments and exact an enormous toll on the patient and family. Remarkable neurobiologic progress has improved the understanding of AD pathogenesisa3 and eventually may result in a diagnostic assay of AD. None now is available. These advances indicate that AD is genetically heterogeneous. Familial AD of early onset ( < 60 years) is associated with mutations in the amyloid-precursor-protein gene on chromosome 213' and with a locus on the long arm of chromosome 14?O Late-onset familial AD98 and sporadic ADa9 have been linked to the apolipoprotein-E4 locus on chromosome 19. A common phenotype (AD) appears to be associated with both allelic and locus genetic heterogeneity. Supported in part by NIA grants AG 03991, AG 05681, AG 06790, and AG 10145. From the Washington University School of Medicine, and The Jewish Hospital of St. Louis, St. Louis, Missouri

CLINICS IN GERIATRIC MEDICINE VOLUME 10 NUMBER 2 MAY 1994

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-'J'here is increasing recognition that AD is also dinicaliy heterogeneous. Current emphasis on the definition of clinical phenotypes may provide new insights into potential etiologic factors and may clarify prognostic and therapeutic variables. A comprehensive clinical classification schema for AD and its heterogeneous aspects has not been developed, however, and diagnostic boundaries and areas of overlap for AD, its variants, and other dementing disorders have yet to be determined. With the emergence of anti-dementia drug therapies for AD,23,31,81 there is renewed impetus for an accurate clinical diagnosis, including a diagnosis for the very early stages of dementia. In the absence of a valid biologic marker, however, definite diagnosis of AD rests on the clinicopathologic correlative methods used by Alois Alzheimer in the classic case description1 of the illness which now bears his name. Because neuropathologic confirmation typically is available only years after diagnostic assessment, presumptive clinical diagnostic criteria for AD and its differentiation from other dementias are needed. Increasing acceptance and use of standard criteria have led to improved diagnostic accuracy for AD and enhanced the scientific foundation for clinical studies of dementia. DEFINITION OF DEMENTIA

A critical first step in the differential diagnosis of AD is to establish the presence of dementia. The Diagnostic and Statistical Manual of Mental Disorders (DSM-111-R) criteria for dementia2 include evidence of deficit in memory and either impairment in at least one other cognitive area (abstract thinking; judgment or reasoning; language; praxis; constructional ability) or personality change. The disturbances in memory and other areas must be sufficient to interfere with usual activities and relationships. A similar definition for dementia is provided by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) Work Group as "the decline in memory and other cognitive functions in comparison with the patient's previous level of function as determined by a history of decline in performance and by abnormalities noted from clinical examination and neuropsychological tests.'"j5 Operationally, because of diminished cognitive ability, a demented patient ability to conduct everyday activities poorly in relation to past performance. DIAGNOSIS OF DEMENTIA Role of Informant

Individuals vary widely in their premorbid cognitive performance owing to differences in native ability, education, and accustomed cognitive demand. Determination of changes in performance presupposes knowledge of prior abilities. This information is generally best provided by a collateral source, usually the spouse or adult child, who is familiar with the

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patient and who has had the opportunity to observe the patient's cognitive performance over time. Structured, informant-based interviews, exemplified by standardized instruments such as the Cambridge Mental Disorders of the Elderly Examination (CAMDEX)a4and the clinical assessment battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD),74have high inter-rater reliability and validity for the diagnosis of dementia, as determined by global clinical ratings and postmortem studies.69 Experience shows that "the patient's self-report of cognitive function bears no relation to cognitive performance whereas the informant's judgment provides a reliable guide."84 SimiIar support for the validity of informant detection of dementia has been reported by

Cognitive Assessment

Mental status testing and neuropsychological examinations objectively document impaired cognition and provide for monitoring of dementia progression. Full-scale neuropsychological batteries measure primary and secondary memory (verbal and nonverbal), language, visuospatial function, problem solving and sequencing ability, attention, and psychomotor performance, including timed tasks. These batteries, therefore, systematically evaluate the major cognitive functions affected by dementia.88,91 Several hours may be required to administer these batteries. Brief cognitive tests are often used at the patient's bedside or in the physician's office to rapidly assess a limited number of cognitive abilities for screening purposes and for follow-up evaluation. The Dementia Scale of Blessed and colleagues6 is an informant-based scale of everyday memory function, ability in daily living activities, and personality, interest, and drive. It remains useful even when the patient is untestable. The Information-Memory-Concentration test6 of the patient measures memory, orientation, facts of common knowledge, and sequencing; a shortened weighted version4a can be completed within 5 minutes. The Mini-Mental State33 measures memory, orientation, concentration, language, and praxis. Significant correlation among these brief cognitive tests has been shown,lo3 indicating that they measure similar aspects of dementia (there also is a high degree of overlap in items). Mini-Mental-State scores correlate with neuropsychologic test perf~rmance.~~ Cognitive measures are part of the standard assessment of dementia65; however, they have several Iimitations. First, performance is sigruficantly influenced by agea6and by race, ethnicity, and education.lo3Second, cognitive tests rarely measure deficits throughout the entire course of dementia (i.e., they have floor and ceiling effects). Third, they often are insensitive to the very mild stages of dementia76in which ranges of performance for normal and affected patients can overlap s ~ b s t a n t i a l l y .The ~ ~ ,diagnosis ~~~ of dementia is based on the clinical judgment that there is cognitive decline sufficient to impair everyday functioning, rather than simply on cognitive test scores.

260

MORRIS

Many features of dementia, including rate of p r o g r e s s i ~ n ,are ~ ~ se,~~ verity dependent. Rarely do all cognitive and functional domains deteriorate at the same rate, however. Global assessments provide an overall dementia severity rating and incorporate noncognitive as well as cognitive functions. Thus, global ratings can be a meaningful measure of patient disability. They are also less subject to floor and ceiling effects than psychometric tests. Many scales are available; some of the more widely used include the Global Deterioration Scalesoand the CAMDEX.s4The Clinical Dementia Rating is another well-known, informant-based ordinal scale which assesses performance in six domains for each of five severity levels: (1)no impairment, (2) questionable impairment, (3) mild impairment, (4) Behavioral scales99evalmoderate impairment, or (5) severe irn~airment.'~ uate noncognitive disturbances, e.g., affective disorder and psychosis, which impair the functional ability of the patient and represent major management problems. DIAGNOSIS OF ALZHEIMER'S DISEASE Criteria

Standardization of clinical criteria for AD by the NINCDS-ADRDA Work Group in 1984 is a notable achievement. This document proposed levels of confidence for the diagnosis of AD. Probable AD is clinically diagnosed "with confidence if there is a typical insidious onset of dementia with progression and if there are no other systemic or brain diseases that could account for the progressive memory and other cognitive deficit^."^^ A clinical diagnosis of possible AD is made when there are variations in the presentation or course of dementia (e.g., disproportionate language disturbance as an early feature) or in the presence of another potentially dementing systemic or brain disorder when AD is believed to be the likely cause of the progressive dementia. A diagnosis of definite AD is reserved for probable AD patients with histopathologic confirmation in which the characteristic lesions of AD, senile plaques and neurofibrillary tangles, are distributed throughout the cerebral cortex (Figure 1). Diagnostic accuracy in clinicopathologicseries for patients meeting criteria for probable AD can exceed 85%.69,75,102 The NINCDS-ADRDA criteria are generally compatible with DSM111-R criteria for primary degenerative dementia of the Alzheimer type.2 Both

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tia and that other causes of dementia are excluded. The presence of a second, potentially dementing disorder, judged not to be the cause of dementia, is allowable in the possible AD category of the NINCDSADRDA criteria but serves as an exclusionary criterion in the DSM-111-R criteria. A task force of the American Psychiatric Association has developed a modified set of criteria for dementia of the Alzheimer type which eliminates personality change as a dementia criterionza;these criteria have

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Figure 1. Bielschowsky stain of the frontal cortex in an Alzheimer's disease brain (original magnification 250X). The thick arrow indicates a neuritic plaque with amyloid core, and the thin arrow indicates a circular neurofibrillary tangle. Other plaques of variable size and more compact tangles are seen in the same field. (Courtesy of Daniel W. McKeel, Jr., MD.)

yet to be finalized. The NINCDS-ADRDA criteria for probable AD and those drafted by DSM-IV are compared in Table 1. Typical Clinical Course

Memory impairment is the major feature of AD, and minor forgetfulness is the usual presenting symptom. Rarely, non-memory deficits such as changes in personality, e.g., withdrawal, or in language, e.g., word-finding difficulties, may herald the disorder. Initial symptoms begin so insidiously that it is difficult to establish a precise date of onset. These changes progress slowly, and in many cases it is several years before the family brings the patient for evaluation. The patient generally has reduced insight and minimizes or denies the memory problem. Common examples of memory impairment in mild cases of AD include failure to recall conversations and details of events and misplacement of items without independent retrieval. Geographic and temporal disorientation may begin at this stage; the patient may need directions to drive to familiar locations. Difficulties with calculation (exemplified by errors in managing household finances), progressive inability to operate appliances (especially if complicated or new), and unsafe driving, e.g., failure to interpret traffic signals or maintain proper indicate impaired attentional, reasoning, and abstractive abilities. Hesitancy in speech with word-finding difficulty and dirninished verbal output may be e ~ i d e n t .Disinterest, ~ ~ , ~ ~ decreased initiative,

262

MORRIS

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NlNCDSlADRDA Probable Alzheimer's Disease'

DSM-IV (proposed) Dementia of the Alzheimer Typet

A. Criteria include: 1. Dementia established by examination and documented by objective testing 2. Deficits in two or more cognitive areas 3. Progressive worsening of memory and other cognitive functions 4. No disturbance in consciousness 5. Onset between ages 40 and 90 6. Absence of systemic disorders or other brain diseases which could account for the progressive deficits in memory and cognition

A. Development of multiple cognitive deficits 1. Memory impairment 2. At least one of the following a. Aphasia b. Apraxia c. Agnosia d. Disturbed executive functioning (planning, organizing, sequencing, abstracting)

B. Diagnosis is supported by: 1. Progressive deficits in language (aphasia), motor skills (apraxia), and perception (agnosia) 2. Impaired activities of daily living and altered patterns of behavior 3. Family history of similar disorders 4. Consistent laboratory results (e.g., cerebral atrophy on computerized tomography)

C. Deficits sufficient to interfere significantly in social and occupational functioning and represent a decline from past functioning

B. Course characterized by continued gradual cognitive and functional decline

D. Other causes (medical, neurologic, psychiatric) of dementia are excluded

'Adapted from McKhann G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human services Task Force on Alzheimer's disease. Neurology 34:939-944, 1984; with permission. tAmerican Psychiatric Association, Committee on Nomenclatureand Statistics: Diagnostic and Statistical Manual of Mental Disorders, ed. 4. Washington, DC, American Psychiatric Association, 1994, pp 142-143, with permission.

and passivity are among the personality changes that may occur in patients with mild AD.'pS5 In contrast, social skills, basic self-care ability, and neurologic function are usually unaffected at this stage; indeed, to casual observers, the patient often appears normal. With progression to moderate AD, memory of recent events is seriously compromised, and only well-learned material is recalled accurately. Day-night disorientation, inability to make purchases or handle money, and progressively restricted function in the home are typical manifestations of this stage. It is difficult for the patient to accomplish even simple chores, such as washing dishes or setting the table, without supervision. Assistance from others is often needed for dressing, including assurance that clothes are changed daily and prevention of inappropriate or duplicate . ....- - _ YLIYVIIUi - - --- - 1 -.-.-- --2- I..^_ LFlICD, h l l ~ UYYLULUIIL C, L.6.f .-1311UIUL6, ing, and bathing, including adjustment of water temperature. Language deteriorates in both comvrehension and outnut. Troublesome behaviors are frequent complications in this stage and may involve suspiciousness; delusions, e.g., belief that misplaced items were stolen or accusations of spousal infidelity; misperceptions; hyperactivity, including restlessness and wandering; verbal and physical aggression; and hallucinati~ns.~~~~ I C IVI 1 l l C l l l l L L l l L L l l l L C VI

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DIFFERENTIAL DIAGNOSIS OF ALZHEIMER'S DISEASE

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These behaviors can be very disturbing for caregivers and may prompt institutionalization of the patient. In patients with advanced AD, total dependence on caregivers is the rule. The patient typically is mute, uncomprehending, and eventually bedridden. Death usually results from intercurrent illnesses associated with vegetative states: marked weight loss and inanition; aspiration; pulmonary embolus; and pneumonia or urosepsis. The total duration of AD from symptom onset to death is highly variable but averages 8 to 10 years.lo7 Clinical Heterogeneity

The broadly described typical clinical course of AD, given above, varies with the severity of dementia and with the individual characteristics of the patient. There are other variations in the clinical pattern of AD. Although it remains possible that AD is a single but complex disease with many subtypes, there is increasing consideration that phenotypic variants reflect different causes which share a common cluster of symptoms, i.e., gradual onset and progression of memory and other cognitive impairment. Selected aspects of the clinical heterogeneity of AD are presented here as an introduction to the rich phenomenology of the disorder; several recent monographs21~70~101~108 provide additional detail. Age at Onset

The prevalance of AD increases exponentially with age, and most studies focus on dementia in the elderly. Although AD generally occurs after age 65, earlier ages at onset (including those in the fourth decade of life) are well d o c ~ m e n t e d .It~remains ~ ? ~ ~ controversial whether early-onset AD is associated with a more rapid progression rate and with disproportionate language i n v ~ l v e m e n t ' ~than , ~ ~ ,late-onset ~~ AD. In the absence of clear evidence to the contrary, current consensus is that early-onset or presenile (onset before age 65 years) and late-onset or senile (onset after age 65 years) AD represent the same clinicopathologic disorder. Nonetheless, the possibility that age at onset modifies clinical manifestations of the illness or reflects etiologic differences has not been conclusively disproved. Family History

Genetic transmission of AD has been established for some families.37,89,90,98 Cases of familial AD are estimated to represent between 20% and 40% of the total AD population, depending on the methods used to identify cases. Although familial AD has been associated with aphasia and other clinical features in some report^,^,"^ a recent comparative study of familial and nonfamilial or sporadic AD did not reveal any significant phenotypic differences between the two forms of the disease.27

264

MORRIS

Extrapyramidai Dysfunction

The extrapyramidal system is commonly involved in AD.35,72The presence of extrapyramidal signs, chiefly bradykinesia and rigidity, in patients with AD has been correlated with diminished functional capacity,15 increased psychosis and other neuropsychiatric disturbance^,^^ and Neuropathologic correlates of the increased rate of cognitive de~line.9~ extrapyramidal syndrome of AD include Lewy-body Parkinson's disease with nigral i n ~ o l v e m e n t , " which ~ ~ ~ ~suggests ~~ potential etiologic interactions between these neurodegenerative disorders. Focal Presentations

Ongoing studies of brain-behavior relationships and multifocal neural networks indicate that caution should be exercised in ascribing cognitive features to specific anatomic sites.68With this caveat, patients occasionally present with seemingly isolated deficits confined to language, visuospatial, perceptual-motor, or behavioral (frontal lobe) domains with corresponding focal cerebral atrophy on neuroimaging studies.13 These isolated deficits often slowly progress to generalized dementia.3,38,50~58 In other patients who present with memory loss and other dementia symptoms, disproportionate language disturbances or visuospatial dysfunction may be an early and prominent feature of AD. Whether in isolation or as part of global dementia, the language disorder typically begins with dysfluency and mild dysnomia; paraphasia, impaired comprehension, dysgraphia, and circumlocution, or empty speech, are additional early features of AD.21Visuospatial disturbances include visual agnosia, impaired figure-ground discrimination, and elements of Balint's syn~lrome.~~,~' AD often is the responsible d i ~ o r d e r , 3 ~but , ~ non-AD ~ * ~ ~ dementias also may present focally. Recognition of these focal syndromes may allow insight into mechanisms that underlie selective vulnerability in cerebral degenerative disease. DIFFERENTIAL DIAGNOSIS OF AD Normal Aging

There is considerable overlap of the mildest cognitive deficits of AD with the cognitive changes of normal aging. The histologic lesions of AD, furthermore, have been reported in apparently nondemented elderly per.I R A Q :.-2 : JVlli),

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of the same clinicopathologic spectr~m.~ In a selected series, 10 patients with only questionable dementia were examined longitudinally by clinical Diagnosis of and psychometric measures until postmortem e~amination.'~ cpeitionable dementia was based i n informant reports of impaired cognitive ability despite "normal" performance on brief cognitive tests and neuropsychological measures; group performance on these measures was not significantly different from controls. At autopsy, all 10 questionably

DIFFERENTIAL DIAGNOSIS OF ALZHEIMER'S DISEASE

265

demented patients had unequivocal AD; in contrast, 4 control patients displayed few, if any, senile plaques or neurofibrillary tangles in the neocortex outside medial temporal lobe s t r ~ c t u r e s . ~These ~ , ' ~ findings suggest that very mild AD can be clinically distinguished from healthy aging. The distinction often rested on the family's report that subtle changes resulted in interference with usual activities for the demented patients, whereas informants for the controls indicated that everyday performance was not appreciably changed even when the control patient noted minor memory complaints, e.g., difficulty in recalling names quickly. More research on brains from well-characterized, longitudinally studied, cognitively healthy and mildly demented persons must be done before definitive conclusions can be reached, particularly in regard to the likelihood of presymptomatic AD (neuropathologically diagnosable disease prior to reaching threshold for clinical manifestation^).^ The development of neuropsychologic measures sensitive to very mild dementia is also needed. Vascular Dementia

After AD, cerebrovascular disease is the most common cause of dementia and is responsible for up to 15% of all pathologically diagnosed Vascular dementia generally is defined cases of dementia (Table 2).46,47,66 by abrupt onset and stepwise deterioration of dementia, in contrast to the insidious onset and gradual progression characteristic of AD. Other features of vascular dementia include history of stroke, focal neurologic signs and symptoms, and vascular risk factors such as hypertension. Although cerebral hypoxia and hemorrhage may result in dementia, ischemic disease is usually the focus in studies of vascular dementia. The concept of vascular dementia implies that cerebrovascular lesions produce cognitive impairment. This is intuitively reasonable; however, the classic studies of Tomlinson and colleagues demonstrate that the occurrence of one or more strokes does not always result in dementia.lo4When dementia does occur, generally a large volume of brain tissue has been destroyed.'05 Depending on the site of the cerebral infarctions, two forms of vascular dementia are sometimes distinguished: multi-infarct dementia (MID), in which multiple completed strokes involve cortical and subcortical areas; and Binswanger's disease, in which the strokes mainly affect subcortical white matter. However, clinical distinction between these forms of vascular dementia is problematic. In general, specific cognitive and behavioral syndromes for vascular dementia are poorly described. A partial explanation for the inadequate clinical characterization may be that criteria for dementia in vascular disease are based on the dementia syndrome of AD, perhaps an inappropriate model for a condition in which cognitive deficits may be patchy rather than Uncritical attribution of dementia to co-existing but noncontributory stroke also has confounded delineation of the clinical syndrome of vascular dementia. White matter changes, which may be caused by both ischemic and nonischemic factors:' frequently are depicted by neuroimaging studies but are of uncertain diagnostic significance.

266

MORRIS

Clinical Diagnosis

Pathologic Diagnosis AD (pure) AD with Parkinson's disease (includes diffuse Lewy body disease) AD with infarcts (includes mixed dementia) AD with other neuropathology Total, AD Vascular dementia (multiinfarct dementia) Parkinson's disease with dementia Nonspecific degeneration CreutzfeldtJakobdisease Pick's disease Progressive subcortical gliosis Brain tumor Other disorders, e.g., multiple sclerosis; WernickeKorsakoff disease; progressive supranuclear palsy No pathology (normal brain)

Dementia* (n = 675) (%)

ADt (n = 650)

AD* (n = 150)

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'Data from Jellinger K, DanielczykW. Fischer P, et al: Cliniwpathologicalanalysis of dementia disorders in the elderly. J Neurol Sci 95239-258. 1990. tData from Mendez M. Mastri AR, Sung HJ, et al: Clinically diagnosed Alzheimer disease: Neuropathe logic findings in 650 Cases. Alzheimer Dis Assoc Disord 1992, 6:35-43, 1992. $Data from Joachim CL. Moms JH, Selkoe DJ: Clinically diagnosed Alzheimer's disease: Autopsy results in 150 cases. Ann Neurol 2450-56, 1988.

Sets of clinical diagnostic criteria for vascular dementia (Table 3) recently have been p r o p ~ s e d ' ~ but , ~are ~ as yet unvalidated. These sets of criteria attempt to identify a causal role of cerebrovascular events in cognitive impairment by requiring that there be a temporal relationship of stroke to the onset or course of dementia. Neuropathologic criteria are needed to determine if the number of strokes, anatomic site of strokes, or cumulative volume of infarcted cerebral tissue are critical factors for vascular dementia.26 Definitive clinicopathologic criteria for vascular dementia, once achieved, should allow examination of the contributory role of stroke in the common situation in which cerebrovascular disease co-exists with AD, so-called mixed dementia. At present, an inability to distinguish association from causality complicates the interpretation of community studies of the relationship between stroke and dementia?4

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Table 3. PROPOSED CLINICAL DIAGNOSTIC CRITERIA FOR VASCULAR DEMENTIA Probable Ischemic Vascular Dementia*

Probable Vascular Dementiat

A. All of the following must be present: 1. Dementia 2. Evidence for: a. Two or more strokes by history, examination, and/or neuroimaging; or b. Single stroke with temporal relationship to onset of dementia 3. Neuroimaging documentation of at least one noncerebellar infarct

A. All of the following must be present: 1. Dementia (in the absence of severe aphasia, psychosis, disturbed consciousness or delirium, major sensorimotor impairment, or other conditions which cause cognitive impairment) 2. Cerebrovascular disease a. Focal neurologic signs consistent with stroke (with or without history of stroke) b. Neuroimaging evidence: 1. Multiple large vessel infarcts or 2. Single strategically placed infarct (e.g., angular gyrus; thalamus; basal forebrain) plus multiple lacunes or extensive periventricular white matter lesions 3. Relationship between 1 and 2 as determined by: a. Onset of dementia within 3 months of stroke or b. Abrupt deterioration or stepwise progression of dementia

6. Supporting evidence: 1. Multiple infarcts in brain regions

important for cognition 2. History of transient ischemic attacks 3. History of vascular risk factors 4. Elevated Hachinski Ischemic Scale score C. Possible supporting evidence: 1. Early gait disturbance and urinary incontinence 2. Excessive T, weighted MRI periventricular white matter changes 3. Focal abnormalities on electrophysiologic studies or functional brain imaging (e.g., PET, SPECT) D. Features neither for nor against the diagnosis: 1. Periods of slowly progressive symptoms 2. Psychotic symptoms (delusions, hallucinations) 3. Seizures E. Features against the diagnosis: 1. Transcortical sensory aphasia without neuroimaging structural correlate 2. Absence of central neurologic symptoms and signs (other than dementia)

B. Features consistent with the diagnosis: 1. Early gait disturbances 2. History of falls 3. Early urinary dysfunction 4. Pseudobulbar palsy 5. Personality and mood changes; abnormal executive functioning C. Features inconsistent with the diagnosis: 1. Early memory and progressive 2. Absence of focal neurologic signs 3. Absence of cerebrovascular lesions on CT or MRI

'Adapted from Chui H, Victoroff HI, Margolin D, et al: Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer's Disease Diagnostic and Treatment Centers. Neurology 42:473-480, 1992; with permission. tAdapted from Roman GC, Tatemichi TK, ErkinjunttiT, et al: Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43250-260,1993; with permission.

268

MORRIS

Parkinson's Disease Dementia occurs in about 25% of patients with Parkinson's disease44; severity of extrapyramidal dysfunction and advanced patient age significantly increase the risk for dementia.28,96The dementia syndrome associated with Parkinson's disease is similar to that of AD in its gradual onset and progression but is more frequently associated with mood disturbances, particularly d e p r e s s i ~ n . ~ ~ In addition to disordered mood, deficits in memory, abstraction, information processing rate, and visuospatial functions7with relative sparing of language are common features of demented Parkinson's disease patients and suggest preferential involvement of frontal-subcorticalsystems.20This notion is supported by evidence of greater nerve-cell loss in rostrally projecting brainstem neurons in the substantia nigra, ventral tegmental area, and locus ceruleus in demented versus nondemented Parkinson's disease patientslll and by the association of biochemical changes and neurofibrillary lesions in the prefrontal cortex of demented patients with Parkinson's disease.lo6Clinicopathologic correlates of the dementia syndrome of Parkinson's disease, however, are heterogeneous and include co-existent AD44 and severe neuron loss in forebrain cholinergic nuclei without AD pathology.14 The presence of Lewy bodies in the cerebral cortex are discussed further on in this article. Although clinical and neuropsychological comparisons of AD and Parkinson's disease suggest that their dementia syndromes are differentF9 there remain substantial areas of overlap for their dementia features. The diagnosis of the dementia syndrome of Parkinson's disease currently rests unsatisfactorily on the secondary development of cognitive impairment in patients with established Parkinson's disease. Diffuse Lewy Body Disease (DLBD)

This syndrome may represent one end of a spectrum of dementiaassociated Lewy body disorders, including Parkinson's disease. Some studies indicate that cortical Lewy bodies are present in all cases of Parkinson's obscuring the pathologic distinction between DLBD and the dementia syndrome of Parkinson's disease. Histopathological descriptions of Lewy bodies in cerebral cortical neurons, where with conventional histologic staining methods they lack the characteristic halo that is an easily recognized feature of Lewy bodies in pigmented brainstem nuclei, have accelerated with increasing - utilization of anti-ubiquitin immuno-L-:-:--

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The clinical of DLBD recently has been characterized.11,12,19,40,64 0ns6t of symptoms, including memory deficit, typically is gradual, but unlike AD, global dementia may have a fluctuating course and is accompanied by psychosis such as visual hallucinations early in the course of dementia. Extrapyramidal dysfunction is often mild and may be levodopa-unresponsive; in contradistinction to the dementia syndrome of Parkinson's disease, cognitive impairment rather than parkinsonism is the

DIFFERENTIAL DIAGNOSIS OF ALZHEIMER'S DISEASE

269

salient feature of DLBD. What role the cortical L e y bodies play in producing dementia is unknown; many cases of DLBD also meet the histologic criteria for AD.40 The relationship among AD, Parkinson's disease, and DLBD is in need of clarification.

Frontal-Lobe Dementia

It is overly simplistic to assume anatomic specificity for individual cognitive functions and behavior^.^^ Nonetheless, frontal-lobe disorders are associated with characteristic clinical deficits, including inflexible thinking, diminished sequencing and organizational or planning abilities, reduced generation of word lists, and impairment of other executive functions. In addition, frontal-lobe lesions can produce striking behavioral changes, including disinhibition, paranoia, lack of insight, emotional lability, irritability, and apathy.20Brains from demented individuals have been reported with only nonspecific degeneration of the frontal or fronto-temporal c ~ r t e xClinical .~ series of these frontal-lobe dementia patients, often with onset prior to age 65, indicate that personality changes overshadow memory Pathologic findings in these cases consist of severe neuronal loss, gliosis, and microvacuolation of upper cortical layers in frontal, anterior temporal, entorhinal, and cingulate cortices in the absence of the histologic lesions of AD, Lewy bodies, or Pick bodies. As cogently posed by Knopman and colleagues51 and echoed by Mann et a1,60 the question remains if frontal-lobe dementia represents a single disease entity or overlaps other disorders, including Pick's disease and motor neuron disease. Descriptive criteria have been proposed53in an effort to improve classification and identify discrete syndromes.

Other Illnesses

There is often great emphasis on identifying treatable causes of dementia. Unfortunately, few cases are completely reversible (Table 4).17The two most common reversible disorders, overmedication and depression, are identified by clinical history and examination rather than by batteries of dementia-screening tests. The cost-effectiveness of specific tests used in dementia batteries is uncertain.55The principle of individualized, selective testing based on clinical judgment following patient evaluation should be employed. Elderly patients are vulnerable to co-morbidities. Even when an associated disorder is not primarily responsible for dementia, it can result in superimposed cognitive and functional impairment and, thus, treatment of the disorder is often appropriate. Both pharmacokinetic and pharmacodynamic alterations occur with age and render older adults more vulnerable to drug effects, including effects of alcohol. A complete drug inventory and, where appropriate, dose reduction and discontinuation of unnecessary medications is indicated in demented patients. Psychoactive agents

270

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REVERSIBLE DEMENTIA

Drugs (including alcohol) Depression Thyroid Vitamin B, deficiency Other metabolic causes Communicating hydrocephalus Subdural hematoma Cerebral tumor Other Total

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'Percentage greater than 100% because of rounding. Reproducedwith permissionfrom ClarfieldAM: The reversible dementias: Do they reverse? Ann Intern Med 109:476-486. 1988

and drugs with anticholinergic properties especially should be used judiciously. The prevalence of dysthyrnia and major depression in community-living elderly is about 3%.79 Depression may be difficult to diagnose in this population because of similarities between depressive features and symptoms of dementia, e.g., passivity.1° Therapy can be effective in alleviating depression, but treatment plans must be individualized to avoid adverse effects. There are many disorders with the potential to cause dementia (Table 5).34Most are uncommon (see Table 2) and are readily distinguished from AD by differences in mode of onset, course of dementia, and the presence of distinctive, associated features. Examples include the subacute onset of cognitive impairment in the "pseudodementia" of depression, a rapid Table 5. CAUSES OF DEMENTIA IN ADULTS BY ETIOLOGIC CATEGORY Cardiovascular disorders Cardiac disorders Multi-infarct dementia Vasculitis Subarachnoid hemorrhage Delayed effects of radiation Vascular malformations Systemic and metabolic disorders Thvroid. ~arathvroid.~ituitarv.adrenal. liver, oulmonarv. Dancreas. kidnev. or blood disorders Sarcoidosis Sjogren's syndrome Systemic lupus erythematosus Fluid and electrolyte abnormalities Hypoglycemia Nutritional deficiencies Hyperlipidemia idiopathic demyelinating disorders Multiple sclerosis

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Table 5. CAUSES OF DEMENTIA IN ADULTS BY ETIOLOGIC CATEGORY (Continued) Toxic disorders Drugs Alcohol Industrial agents Pollutants Heavy metals (Pb, Hg, Mn, Ar, Th, Al, Sn, Bi) Carbon monoxide Affective disorders Depression Trauma Subdural hematoma Dementia pugilistica Seizure disorders Infectious disorders Meningitis Encephalitis (including human immunodeficiency virus infection and Lyme disease borreliosis) Brain abscess Syphilis Whipple's disease CreutzfeldtJakob disease Gerstmann-Straussler-Scheinkerdisease Kuru Neoplastic disorders Direct and indirect effects of primary and metastatic tumors Hydrocephalus Normal pressure hydrocephalus Obstructive hydrocephalus (aqueductal stenosis) Sensory deprivation Degenerative disorders Alzheimer's disease Pick's disease Multiple system atrophy Parkinson's disease Progressive supranuclear palsy Progressive subcortical gliosis Amyotrophic lateral sclerosis with dementia Amyotrophic lateral sclerosis-parkinsonismdementia complex Cortical-basal ganglionic degeneration Frontal lobe dementia Adult-onset neuronal intranuclear hyaline inclusion disease Diffuse Lewy body disease Genetic disorders Cerebellar/spinocerebellar ataxias Dentatorubral-pallidoluysian atrophy Familial mineralization of brain vessels (e.g., Fahr's disease) Gangliosidoses (GM2) Halleruorden-Spatz disease Huntington's disease Kufs' disease (neuronal ceroid lipofuscinosis) Lafora's disease MachadoJoseph disease (Azorean disease) Mitochondria1 encephalopathies Myotonic dystrophy Porphyrias Wilson's disease Adapted from Friedland RP: Alzheimer'sdisease. Clinical features and differential diagnosis. Neurology 43:S45-S51, 1993; with permission.

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course with deatle1general!,y occijl-jng vj,t&in a year of onset for .creutzfelclt-fakob disease, and supranuclear gaze palsy and gait and postural disturbances in progressive supranuclear palsy. A fuller discussion of individual rare dementing illnesses is not possible here; the interested reader may find additional information in several recent monographs.21,70~101~108 SUMMARY

AD is by far the leading cause of dementia, accounting for about 75% of cases. Vascular dementia and Parkinson's disease, with or without concomitant AD, are responsible for much of the remainder of pathologically confirmed causes of dementia. The differential diagnosis of AD remains clinically based; even in the absence of a biologic marker for the disease, diagnostic accuracy can be high. Informant interviews can be helpful in detecting early dementia and in distinguishing the various stages and features of AD. Characterization of phenotypic variants of AD and refinement of diagnostic criteria for the non-AD dementias is needed to clarify the inter-relationships of these conditions and facilitate molecular genetic and other basic investigations of the etiopathogenesis of AD. ACKNOWLEDGMENTS Virginia Buckles, PhD, and Jennifer Zieleskiewicz provided editorial assistance. Linda Vaughn and Jane McGrath expertly typed the manuscript.

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